title: RON confers lapatinib resistance in HER2-positive breast cancer cells.
abstract: Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d'Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Quanren
authors.initials: Q
authors.lastname: Wang
authors.forename: Haitian
authors.initials: H
authors.lastname: Quan
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Chengying
authors.initials: C
authors.lastname: Xie
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
mesh_terms: D000813:Anilides / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab
chemical_list: D000813:Anilides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077547:Crizotinib; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C544831:GSK 1363089; C508053:ERBB2 protein, human; C080835:RON protein
keywords: HER2; HER2-targeted agents; Lapatinib resistance; RON